Numerous automated clinical analyzers are known and widely used in hospital clinical laboratories. An example of such an analyzer is the multi-channel type analyzer.
A multi-channel analyzer is one in which a series of different tests are performed simultaneously by the analyzer, and in parallel with one another. Such an analyzer can be best visualized as a series of batch analyzers operating in parallel wherein each channel performs a single analysis test. The multi-channel type analyzer generally utilizes a liquid reagent to react with the particular constituent being tested in the sample and a photo-optical system to read the optical absorbance of the sample which corresponds to the level of the constituent in the sample.
Although this type of automated analyzer has received wide acceptance in the clinical laboratory, certain drawbacks are associated with its use. For example, although the multi-channel type analyzer is reliable due to its simplicity, cost effective for large number of samples and has a relatively high test throughput rate, it is limited in the sense that it can only be effectively utilized to perform a single constituent analysis at a time on a relatively large number of samples. In addition, such analyzers are not capable of performing emergency "stat" tests due to their relatively long and complex set up time and their inherent inability of economically analyze a single test sample.
A further significant disadvantage found is that although they can simultaneously perform tests for multiple constituents on the same sample, generally all of these tests must be performed for every sample whether desired or not. This results in a waste of both sample material and the reagents used in the unnecessary tests. Furthermore, due to the fact that multiple discrete and dedicated channels are utilized in such an instrument, there is significant duplication of numerous components which adds to the complexity and expense of the overall instrument.
An automated single track clinical analyzer which avoids the above-described in commonly owned U.S. patent application Ser. No. 284,840, filed July 20, 1981, now abandoned, entitled, "Automated Analysis Instrument System", the disclosure of which is hereby incorporated by reference in its entirety herein. By way of contrast to the multi-channel analyzer, the single track analyzer has both discrete and profile capabilities. The single track analyzer can perform different analytical profiled (i.e., profile analysis) or the same analytical test on a series of different patient samples (i.e., batch analysis). In either mode of the single track analyzer, the cuvettes containing samples are processed serially along a single track within the analyzer. The single track analyzer is capable of performing multiple selected tests on a single specimen and is adapted for handling "stat" testing of emergency samples and routine chemistries. To this end the analyzer is adapted to dispense different permutations of reagent and liquid biological sample into successive relatively small cuvettes advanced therethrough and has multiple analysis stations to which the cuvettes are fed in turn so that examination of the treated samples can be effected at varying time intervals without limiting the throughput of the instrument. These multiple analysis stations permit their positioning at read times that are closely related to theoretical optimal kinetic and endpoint reaction read times. Furthermore, by using a unique photo-optical system, also described in commonly owned U.S. patent application Ser. No. 284,841, filed July 20, 1981, now U.S. Pat. No. 4,477,190, entitled "Multichannel Spectrophoto- meter", the disclosure of which is hereby incorporated by reference in its entirety herein, greater flexibility of analysis at each analysis station is achieved. This is because the photo-optical system employs fiber optic bundles or similar light guides to transmit variable wavelengths of light to each analysis station from a single light source.
The single track analyzer utilizes a disposable cuvette belt formed from thin plastic film and defining a series of discrete reaction compartments (cuvettes) which are transported in line ahead through the instrument. The cuvettes are relatively small; they are generally for example capable of holding a final reaction volume of approximately 300 microliters. The patent sample in the cuvette is approximately 2020 microliters. Such a cuvette belt is described in commonly owned U.S. patent application Ser. No. 284,842, filed July 20, 1981, now abandoned, entitled, "Cuvette System For Automated Chemical Analyzers", the disclosure of which is incorporated in its entirety by reference herein. Such a belt provides handling flexibility and avoids the cross-contamination associated with flow-through cuvettes as well as avoiding the washing required of reusable cuvettes.
The earlier clinical analyzers discussed above employed liquid reagent, and mixing of the reagent with the diluent prior to addition of the biological sample was achieved by shooting a stream of the liquid reagent into the cuvette so as to produce a vortex-type mixing process. A preferred feature of the analyzer disclosed in U.S. patent application Ser. No. 284,840 is that it is adapted to utilize dry particulate reagents, preferably in tablet form, which are dispensed into the cuvettes from a rotating carousel which can hold a large number of doses. A preferred embodiment of tablet dispenser is described in commonly owned U.S. patent application Ser. No. 285,022, filed July 20, 1981, now U.S. Pat. No. 4,405,060, entitled, "Tablet Dispensing Device", the disclosure of which is hereby incorporated by reference in its entirety by reference herein. In order to effect dissolution of the dry particulate reagent within the diluent prior to addition of the biological sample, the reagent and diluent are mixed by ultrasonic means.
A further advantageous feature of such an automated clinical analyzer is the use of microprocessor control, particularly for the dispensing and analysis station and the loading and transfer assembly for presenting to the analyzer containers having the samples to be tested.
A particular embodiment of the automated single track clinical analyzer according to aforesaid U.S. patent application Ser. No. 284,840 is the subject of the Paramax Analytical System manufactured by American Dade, a division of American Hospital Supply Corporation, of Miami, Fla. "Paramax" is a registered trademark of American Hospital Supply Corporation. In this system, which is under microprocessor control, a cuvette belt is cut into sections, comprising one or several cuvettes, which are fed in turn past a reagent tablet dispenser, a diluent dispenser, an ultrasonic horn for mixing the reagent and diluent, a sample dispenser and eight photo-optical analyzer stations. During their passage through dispensing and analysis, the cuvettes are supported in a water bath kept at a constant temperature and after analysis they pass through a sealing station and into a disposal station.
Reagent tablets are dispensed from a rotary carousel and the biological liquids to be sampled are delivered in tubes to the sample dispenser one at a time by a carousel having priority access positions to allow immediate "stat" sample entry. Codes on the tubes identify the samples and a code-reader alerts the microprocessor to operate the analyzer in accordance with the coded information. A further reagent dispenser is arranged between two of the analyzer stations for producing further sample reaction to permit additional analysis.
In the prior clinical analyzers as described above, the reagent and diluent are mixed in the cuvette prior to the addition of the liquid biological sample, either by shooting the reagent into the diluent to form a vortex in the case of a liquid reagent or by ultrasonic mixing in the case of the dry particulate reagent. Various improvements over such prior clinical analyzers have been disclosed in commonly owned U.S. application Ser. No. 575,924 filed Feb. 1, 1984, now abandoned entitled "Clinical Analysis Systems and Methods", the disclosure of which is incorporated herein in its entirety by reference.
It has been found, for example, that improved reliability and controllability of the analysis of the samples can be achieved by again mixing the contents of the cuvette after addition of the sample by directing an air jet to an acute angle against the surface of the liquid in the cuvette. Particularly good mixing is obtained where the air jet is directed at the liquid surface adjacent its junction wit the wall of the cuvette. The optimum point of contact of the air jet with the liquid surface has been found to be at the meniscus formed at the junction between the liquid surface and the wall of the cuvette.
The combination of directing the air jet against the liquid surface adjacent its junction with the wall of the cuvette and directing it at an acute angle to the surface producing a horizontal component has the beneficial effect of creating a vortex which produces a thorough mixing of the contents of the cuvette. Thus, a whirling or circular motion is induced in the contents tending to form a cavity of vacuum in the center and to draw the materials at the edge towards the center thus providing an effective mixing action. Particularly where the air jet hits the contents of the cuvette in the meniscus region, the contents tend to be raised up the wall of the cuvette opposite where the air jet hits the contents creating a particularly effective vortex producing very good mixing of the sample with the diluent and reagent. Thus a particulate reagent will become totally suspended within the diluent and the sample optimizing the reaction of the sample therewith.
By controlling the level of liquid in the cuvette and the air jet, splashing of the contents out of the cuvette leading to intercuvette contamination can be avoided. Splashing can, for example, be avoided by controlling the pressure of the air jet and/or by pulsing the air jet on and off.
The air jet may be directed at the liquid surface in the cuvette from a nozzle arranged inside the cuvette, but, in a preferred embodiment, the air jet is directed into the cuvette from outside the cuvette. Thus, a cuvette partially filled with the diluent, reagent and sample is disposed beneath an inclined nozzle and an air jet is directed at the liquid surface in the cuvette adjacent its junction with the wall of the cuvette from the nozzle.
In an automated system, the cuvette is partially filled to a predetermined liquid level and then advanced into alignment stationarily beneath a fixed nozzle so that the latter is aimed at the junction of liquid surface and cuvette wall. The angle of the air jet nozzle should ideally be as far as possible from the vertical providing maximum horizontal components of the air jet upon the liquid. The angle is determined by the diameter of the cuvette, the liquid level in the cuvette, which is itself controlled by the requirement to avoid splashing of the contents out of the cuvette, and the position of the nozzle over the mouth of the cuvette.
To obtain the optimum angle, the nozzle should be arranged diametrically opposite the point at which the air jet hits the liquid surface. Thus, in a preferred embodiment, the liquid level in the cuvette is suitable about 15 mm to about 25 mm below the mouth of the cuvette with the nozzle arranged to direct the air jet at an angle of between about 75 degrees and about 80 degrees to the liquid surface (horizontal), the cuvette being arranged vertically. When the cuvette has an elongated cross-section, the air jet is suitably aligned with the longer cross-sectional dimension.
The cuvette may be tilted towards the nozzle to permit the angle of the nozzle to be more horizontal.
It has been found that activation of the air jet for a period of between about 3.5 seconds, and about 4.5 seconds, preferably about 4 seconds, is usually sufficient to provide good mixing of the diluent, reagent and sample.
Numerous advantages are inherent in the apparatus and methods disclosed in the aforesaid application Ser. No. 575,924. It permits thorough mixing of the reagent, diluent and sample which enhances reliability and controllability of the test(s) of the sample. The mixing process occurs in a very fast timeframe. Intercuvette contamination is avoided by controlling the mixing action so hat splashing of material out of the cuvette is prevented. There is no physical contact between the nozzle and the contents of the cuvette and by having the nozzle arranged outside the cuvette, contamination of the nozzle is avoided and there is no need to move any component into the cuvette to effect the mixing, thus maximizing throughput in an automated process.
While it is preferred, particularly in an automated process, that the air-jet nozzle direct air into the cuvette from outside the cuvette, it is also possible to direct the air jet from inside the cuvette and aimed at the liquid surface from a position above the liquid surface. While requiring insertion and removal of the nozzle into and out of the cuvette (either by lowering and raising the nozzle or by raising and lowering the cuvette) this does have the advantage that the nozzle can be angled more closely to the horizontal without spilling of the contents. Thus, the nozzle may be inclined at an angle of between about 0 degrees to about 90 degrees to the horizontal, with the preferred embodiment of between about 8 and 15 degrees. Depending upon the height of the nozzle above the liquid surface, it may become contaminated by the liquid as it is agitated in which case it should be cleaned with diluent between mixing operations. It will be noted that in both instances, the nozzle is arranged above the liquid surface and is therefore noninvasive of the liquid.
Such an automated analyzer system may incorporate any or all of the features described in aforesaid U.S. patent application Ser. No. 284,840. Thus, a dry particulate reagent, preferably in tablet form, is dispensed into the cuvette together with a diluent and subject to ultrasonic mixing to effect dissolution of the reagent and dispersal in the diluent. A second, liquid reagent may be added at the same time as the diluent. The system has multiple analysis stations, having a photo-optical system as described in aforesaid U.S. patent application Ser. No. 284,841 to which the cuvettes are fed in turn. A further reagent dispenser is arranged between two of the analysis stations and a further mixing station, according to the invention, is arranged immediately following this dispenser which acts on each cuvette into which further reagent (preferably liquid) has been dispensed by directing an air jet against the liquid surface adjacent its junction with the cuvette wall to enhance further reaction of the sample.